ERα-targeted endocrine therapy, resistance and the role of GPER

Area of Science:

• Endocrinology
• Oncology
• Pharmacology

Background:

• Endocrine therapy is a primary treatment for estrogen receptor alpha (ERα)-positive breast cancers.
• Tumor relapse due to endocrine resistance is a significant clinical challenge.
• Constitutively active ERα mutants and G protein-coupled estrogen receptor (GPER) activation contribute to endocrine resistance.

Purpose of the Study:

• To highlight the need for novel anti-hormone drugs targeting ERα-positive breast cancers.
• To emphasize the importance of developing selective estrogen receptor modulators (SERMs) and downregulators (SERDs) that overcome endocrine resistance.
• To underscore the necessity of screening new drugs for cross-reactivity with GPER.

Main Methods:

• Review of mechanisms of endocrine resistance in ERα-positive breast cancer.
• Analysis of the role of ERα mutants and GPER in treatment failure.
• Discussion of drug development strategies for next-generation anti-hormone therapies.

Main Results:

• Constitutively active ERα mutants are a key mechanism of endocrine resistance.
• GPER activation by existing SERMs/SERDs can contribute to endocrine resistance.
• A subset of relapse tumors harbor ERα mutants, necessitating new therapeutic approaches.

Conclusions:

• Truly ERα-selective SERMs and SERDs are required for effective treatment of ERα-positive breast cancers.
• Next-generation endocrine therapies must be screened for GPER activity to avoid cross-reactivity.
• Developing drugs that specifically target ERα without affecting GPER is crucial for overcoming endocrine resistance.